(261) Concentrations of elexacaftor/tezacaftor/ivacaftor across the cystic fibrosis population: interim analysis of the CHEC-Pharmacokinetics study

Background: Mutation-specific CFTR modulators targeted to molecular defects in the CFTR protein has improved the care of people with cystic fibrosis (pwCF). Despite the success of highly effective modulator therapy, there is still variance in drug efficacy. The CHEC-SC Study (Characterizing CFTR modulated changes in sweat chloride and their association with clinical outcomes) is an ongoing multi-center epidemiologic study of sweat chloride measurements from people with CF treated with the triple combination (TC) modulator therapy (elexacaftor, tezacaftor, and ivacaftor). In CHEC-Pharmacokinetics (CHEC-PK), we evaluated plasma concentrations each compound in a real-world population of patients taking TC.

Methods: Six sites of CHEC-SC participated in the CHEC-Pharmacokinetics (CHEC-PK) study, enrolling adult and pediatric participants age ≥ 6 years receiving TC. Whole blood was collected at 0h (prior to ingestion of TC) and 4 hours (4h) post-dose. Sweat chloride was also measured. Time of TC ingestion over the prior 24 hours was recorded.

Results: For this interim analysis, we report modulator concentrations observed in 70 participants. Median (range) reported time between morning (TC) and evening (ivacaftor) doses was 12 hours (8-13.5). The median (range) concentrations for elexacaftor, tezacaftor, and ivacaftor at 0h were 2687 ng/mL (0 – 20,319); 1763 ng/mL (5.5 – 11,365); and 538 ng/mL (0 – 2735), with coefficients of variation (CV%) of 73%, 86%, and 78%, respectively. Median values at 4h for elexacaftor, tezacaftor, and ivacaftor were 8288 ng/mL (428 – 23891); 5675 ng/mL (414 – 11,416); and 1261 ng/mL (17 – 3655) with CV% of 52%, 35%, and 54%, respectively. Seven participants (10%) had one or more concentrations that were lower at 4h compared to 0h. During development, the effective concentration to elicit ~50% of the maximal clinical response (EC₅₀) and 90% (EC₉₀) are determined and represent minimum thresholds for exposure required to elicit a clinical response.(1) The percent of patients with 0h concentrations between these values is 14% for ivacaftor; 72% for tezacaftor; and 48% for elexacaftor. Seventy-seven percent of samples for ivacaftor, 20% for tezacaftor, and 46% for elexacaftor were above the EC₉₀; 9% of samples for ivacaftor, 8% for tezacaftor, and 6% for elexacaftor were below the EC₅₀, including 5 with concentrations near zero. At 4h, the majority of patients had concentrations above the EC₉₀ (83%, 84%, and 91% respectively).

Conclusions: In this study of pwCF taking TC, we found a small percentage of patients with concentrations below that expected to elicit a minimal clinical response at 0h. In contrast, the majority of patients likely maintain concentrations above the EC₉₀ threshold. However, more than 10% of pwCF in this study have concentrations of all three compounds at 0h that are well above the EC₉₀, 3x higher in the case of ivacaftor. These data suggest some patients may tolerate a dose reduction, especially for ivacaftor, which would be unlikely to impact clinical response and may aid in managing side effects. Next steps for this study will test associations between drug concentrations and sweat chloride, as well as associations with genetic variants in relevant pharmacogenes.

Acknowledgements: This work was supported by the Cystic Fibrosis Foundation, GUIMBE20K0 to J.S.G., and HAMBLE17K0 to N.M-H.

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